Water and cardiovascular balance are critical to survival, and vasopressin (VP) plays a critical role in water reabsorption and blood pressure maintenance during dehydrational, hypotensive or hypovolemic challenge. Dysregulation of VP factors into a range of diseases, from diabetes insipidus and hypernatremia (VP deficiency) to hypertension (excessive release). VP is produced in the magnocellular neurosecretory system of the hypothalamus, where neurons in the supraoptic and paraventricular nuclei synthesizing VP and oxytocin (OT) send axons to the posterior pituitary gland to terminate in the neurohemal contact zone. From these axon terminals, VP and OT are released into the blood stream for effects at distal organs, such as kidney, vascular smooth muscle, mammary gland and uterus. Release is a function of the frequency and pattern of the action potential trains of these neurons when excited. VP neurons adopt an asynchronous, phasic bursting discharge pattern that maximizes hormone release per spike (referred to as facilitation) and avoids secretory fatigue (when release abates during continued activity). The phasic bursting pattern further codes VP release by altering the spike frequency within these bursts, burst duration, and interburst interval. Optimal parameters are burst lengths and interburst intervals each lasting ~20 sec, mean rates within each burst of 12-13 Hz. A key feature to the control of VP neuron phasic bursting is the unique role played by somatodendritically released VP, which operates on VP autoreceptors on the neurons. Autoregulation may be manifest by both direct membrane and synaptic effects of VP. Our guiding hypothesis is that locally released VP tunes the VP neurons to the optimal discharge pattern by varying its effect according to ongoing activity. Thus VP would be excitatory to less active neurons, and inhibitory to those exceeding optimal burst parameters. In three specific aims the project will explore the basis for VP[unreadable]s biphasic effects, focusing on intracellular calcium as a key player and/or the possibility that two different VP receptors code these opposing effects. Aim 1 will focus on the effects of VP on VP neuronal firing pattern;Aim 2 examines the direct effects of VP on the intrinsic properties of VP neurons, especially calcium currents and the calcium-dependent potentials that regulate firing;Aim 3 explores the role of synaptic activity, and its modulation by VP, in phasic bursting Modulation by VP. The broader impact of the work relates to the fact that many neurons in the brain autoregulate their activity, and the results here will influence the direction of work in other parts of the central nervous system. Furthermore, phasic, bursting activity is exhibited in many neurons and endocrine cells, so the mechanisms we uncover may aide in the general understanding of patterned activity.